Worldwide, an estimated half a million head & neck cancer cases and 300,000 deaths due to head & neck cancer occurred in the year 2000. Increasing incidence among young individuals, especially for tongue carcinomas, has been reported in the US and Europe. While it is well-established that tobacco and alcohol account for at least 75% of head & neck cancers, important etiologic questions remain to be addressed: (i) the role of low penetrance genetic susceptibility factors (e.g. SNPs) and their interactions with environmental factors, (ii) etiology in rare subgroups including young age at onset, and nonsmokers and nondrinkers, (iii) the effect of human papillomavirus (HPV), particularly with respect to cancer subsite. Novel approaches are necessary to overcome the limitations in previous studies of these issues, and in particular the constrained sample sizes. We recently established the international Head and Neck Cancer Epidemiology (INHANCE) Consortium as one such approach, based initially on the collaboration of 10 research groups leading large molecular epidemiology studies of head & neck cancer. The consortium provides questionnaire information and biological samples from 9,000 case-control pairs at present. Upon completion of all studies in 2006, there will be 14,000 case-control pairs; which may further increase with the inclusion of additional studies. As a first step for the consortium, we will conduct two sets of pooled analyses on: (i) young subjects, (ii) nonsmokers and nondrinkers. Our specific aims are: 1) for young onset head & neck cancers, to test the hypotheses of a lesser role of tobacco and alcohol habits, and a stronger role for family history of cancer, marijuana use, smokeless tobacco, and sexual history, 2) to identify the relationship of tobacco in nondrinkers, of alcohol in nonsmokers, and the etiologic roles of marijuana use, passive smoking and low body mass index independent from those of tobacco and alcohol for head & neck cancer, 3) to obtain from all studies, questionnaires and lists of SNPs being genotyped to evaluate data comparability across studies for further joint applications. Future directions for the consortium will be to coordinate genotyping from a list of priority SNPs and to assess the effect of HPV infection. We anticipate that the INHANCE consortium will be a major step toward improving our understanding of the causes and mechanisms of head & neck cancers and the beginning of a long-standing cooperation.